The biological and chemical sciences, much like the electronics industry, have sought to gain advantages of cost, speed and convenience through miniaturization. The field of microfluidics has gained substantial attention as a potential solution to the problems of miniaturization in these areas, where fluid handling capabilities are often the main barrier to substantial miniaturization.
For example, U.S. Pat. Nos. 5,304,487, 5,498,392, 5,635,358, 5,637,469 and 5,726,026, all describe devices that include mesoscale flow systems for carrying out a large number of different types of chemical, and biochemical reactions and analyses.
Published international patent application No. WO 96/04547 to Ramsey describes microfluidic devices that incorporate electrokinetic means for moving fluids or other materials through interconnected microscale channel networks. Such systems utilize electric fields applied along the length of the various channels, typically via electrodes placed at the termini of the channels, to controllably move materials through the channels by one or both of electroosmosis and electrophoresis. By modulating the electric fields in intersecting channels, one can effectively control the flow of material at intersections. This creates a combination pumping/valving system that requires no moving parts to function. The solid state nature of this material transport system allows for simplicity of fabricating microfluidic devices, as well as simplified and more accurate control of fluid flow.
Published international patent application No. WO 98/00231 describes the use of microfluidic systems in performing high throughput screening of large libraries of test compounds, e.g., pharmaceutical candidates, diagnostic samples, and the like. By performing these analyses microfluidically, one gains substantial advantages of throughput, reagent consumption, and automatability.
Despite the above-described advances in the field of microfluidics, there still exist a number of areas where this technology could be improved. For example, while electrokinetic material transport systems provide myriad benefits in the microscale movement, mixing and aliquoting of fluids, the application of electric fields can have detrimental effects in some instances. For example, in the case of charged reagents, electric fields can cause electrophoretic biasing of material volumes, e.g., highly charged materials moving at the front or back of a fluid volume. Solutions to these problems have been previously described, see, e.g., U.S. Pat. No. 5,779,868. Alternatively, where one is desirous of transporting cellular material, elevated electric fields can, in some cases, result in a perforation or electroporation, of the cells, which may affect their ultimate use in the system.
In addition to these difficulties of electrokinetic systems, microfluidic systems, as a whole, have largely been developed as relatively complex systems, requiring either complex electrical control systems or complex pump and valve systems, for accurately directing material into desired locations. Accordingly, it would be generally desirable to provide microfluidic systems that utilize simplified transport systems, but that are also useful for carrying out important chemical and/or biochemical reactions and other analyses. The present invention meets these and a variety of other needs.
In a first aspect, the present invention provides for a method of monitoring a time-dependent reaction. The method comprises introducing first and second reagents into a first flow channel wherein the reaction is initiated with respect to at least a first reagent, to form a first reaction mixture. The first mixture is transported along the flow channel, past a detection zone which detects an extent of the reaction. The flow rate of the first mixture is varied along the flow channel to vary an amount of time between mixing of the first and second components and detection of the extent of the reaction at the detection zone. The result of an interaction is then monitored between the first and second reagents.
Another aspect of the present invention is a system for monitoring a time dependent reaction. The system comprises a body containing at least a first flow channel. The first flow channel is fluidly connected to a source of a first reagent and a source of a second reagent. A flow controller is operably coupled to the flow channel, which contains programming to provide a varying flow rate of a fluid into and through the flow channel.